Obstetrics and Gynecology

Myasthenia gravis

Myasthenia Gravis

1. What every clinician should know

Clinical features and incidence

Myasthenia gravis (MG) is an autoimmune disorder characterized by weakness and decremental response on repetitive use of skeletal muscles. It is caused by the development of auto-antibodies directed against the nicotinic acetylcholine receptor in the post synaptic portion of the neuromuscular junction.

There are two clinical forms of MG: ocular and generalized. In ocular MG (OMG), the weakness is limited to the eyelids and extraocular muscles. In generalized disease, the weakness may also affect the ocular muscles, but it also involves a variable combination of bulbar, limb and respiratory muscles. It is a rare disease with prevalence ranges from 50-125 cases per million population. Myasthenia gravis affects twice as many women as men, with the peak incidence in women occurring in the third decade of life.

The long term outcome of MG is not altered by pregnancy and disease course is highly variable, with exacerbations occurring equally in all three trimesters. 41% of women have exacerbations during pregnancy, with remission in 29% and no change in the disease course in the remaining 32%. Postpartum exacerbations occur in approximately 30% of women.

The mortality risk is highest during the first year, so it is recommended that the myasthenic patient delay childbirth for the first year or two after diagnosis.

Cardinal features include fluctuating weakness and easy fatigability of skeletal muscles without reflex, sensory or coordination abnormalities. This is usually followed by bedside tests and confirmed with electromyography studies. Many cases begin with ocular muscles alone, but usually there is progression of weakness to bulbar muscles involved in swallowing and chewing. Over 85% of the time, limb muscles are involved, often in a proximal distribution.

The fatigue is manifest by repetitive use of the muscle, not by a sense of being “tired.” The majority of patients present with ocular symptoms of ptosis and/or diplopia. Muscles of jaw closure are often involved and produce weakness with prolonged chewing. Dysarthria and dysphagia may also be present if oropharyngeal muscles are involved. When facial muscles are affected, the patient may appear expressionless. In some cases, the weight of the head may overcome the extensors of the neck, producing a “dropped head syndrome.”

The clinical course is characterized by periods of remissions and exacerbations. Physical stressors such as infection and surgery may trigger disease progression. An MG crisis is defined by weakness of respiration becoming severe enough to require assisted ventilation.

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

The diagnostic approach should begin with a detailed history and physical exam. Once the diagnosis is suspected by history, physical exam and administration of acetylcholinesterase agents, it should be confirmed by electrophysiologic studies. Although the detection of auto-antibodies in patients with MG is helpful, they may not be detected in patients with ocular disease.

If the diagnosis of MG is strongly considered or confirmed in a pregnant patient, further evaluation should be pursued. This includes a baseline assessment of motor strength, respiratory status and pulmonary function tests. Cardiac status should be followed with ECGs, since rare occurrences of focal myocardial necrosis have been recorded in these patients.

Several diagnostic tests aid in the diagnosis of MG, including a response to acetylcholinesterase agents. Administration of edrophonium or neostigmine will result in a transient increase in muscle strength in the myasthenic patient. Edrophonium is preferable secondary to its rapid onset and short duration. These preliminary tests have a high false positive rate.

Electro-diagnostic testing confirms the diagnosis of MG with a characteristic abnormal decline in the size of evoked muscle potentials noted on repetitive supermaximal muscle motor nerve stimulation. Serum auto-antibodies to human muscle acetylcholine receptors can be demonstrated in 70-90% of patients, however these autoantibodies are only detected in 15% of patients with ocular MG.

Myasthenia gravis can be found with Hashimoto’s thyroiditis, rheumatoid arthritis, polymyositis-dermatomyositis and sarcoidosis, so appropriate diagnostic tests for these conditions should be ordered when considering the diagnosis of MG. This includes TSH, free T4, thyroid stimulating/inhibiting antibodies, rheumatoid factor and MRI, electromyography, muscle biopsy, creatine kinase, and aldolase for polymyositis-dermatomyositis.

Differential diagnosis

When considering an MG diagnosis, other neuromuscular conditions including mitochondrial myopathies, thyroid ophthalmopathy and Lambert Eaton myasthenic syndrome must be excluded. In MG, reflexes are normal; in Lambert Eaton syndrome, however, reflexes are depressed. Medications such as penicillamine are known to cause MG and discontinuation should lead to resolution of disease within 1 year.

3. Management

Anticholinesterase agents are used as first line agents, with pyridostigmine being the most commonly used. The management of MG should not be altered during pregnancy. These drugs need to be titrated with caution secondary to higher doses precipitating weakness. Although beneficial, the therapeutic effects of these medications wax and wane after prolonged treatment. Normal physiologic changes associated with pregnancy may affect medication efficacy.

Nausea and vomiting may require parenteral therapy. The increase in blood volume and changes in renal clearance may call for adjustments in dosing. If an increase in dosing is indicated, the interval should first be shortened before dosage is increased. Surgical thymectomy is often beneficial, with clinical remission noted in up to 45% of patients after the thymus was surgically removed.

Immunosupressive therapy is indicated when symptoms are not controlled with anticholinesterase medications. Prednisone, azathioprine and cyclosporine are commonly used. Azathioprine and cyclosporine are linked with small, but increased risks of spontaneous abortion, preterm labor, teratogenicity and growth restriction.

In the case of severe MG requiring these agents, the benefit may outweigh the risks. Whereas corticosteroids can be used safely during lactation, all the other immunosupressive agents can cause immunosupression in the infant, so breastfeeding should be discouraged. Breastfeeeding is acceptable for women on anticholinesterase medications since these medications are found to be secreted in low levels in breast milk. However, high doses may lead to muscarinic side effects in the newborn.

Physical stressors such as infection and surgery may trigger disease progression, so all infections should be treated expeditiously. In addition, complaints of cough or dyspnea should be promptly addressed since this can lead to a myasthenic crisis.

Approximately 75% of myasthenic patients have thymic abnormalities and 10% of these have a thymoma. Since 30% of thymomas are invasive at the time of diagnosis, all thymomas should be surgically removed. An enlarged thymus can be found via computed tomography (CT) and magnetic resonance imaging (MRI).

Antepartum assessment

Fetal assessment tests that rely on alterations of fetal movement or heart rate response to fetal movement are not always reliable in the myasthenic patient. This includes the patient’s perception of fetal movement. The oxytocin challenge test may be required to detect fetal hypoxia. Continuous fetal monitoring of a viable fetus is indicated during a myasthenic crisis because the patient and fetus may be hypoxic. Abnormal fetal sonographic findings include polyhdramnios due to impaired swallowing, decreased fetal movement and in rare cases, fetal arthrogryposis multiplex congenita. This syndrome is described as a lack of fetal movement, diaphragmatic excursion, joint contractures and pulmonary hypoplasia.

Labor and Delivery

The first stage of labor is not affected by myasthenia gravis since the uterus is comprised of mainly smooth muscle and does not involve the acetylcholine receptor mechanism for contraction. However, the second stage may lead to rapid fatigue due to expulsive efforts demonstrated by the mother. An operative vaginal delivery is an option to help reduce second stage maternal fatigue and weakness. Excessive exertion and pain should be avoided as it can lead to pulmonary deterioration and need for mechanical ventilation.

Cesarean delivery should be reserved for the usual obstetrical indications or for women with respiratory compromise and need for ventilatory support during delivery. A pulse oximeter should be placed early in the labor course in women with MG and frequent assessment of respiratory rate should be part of intrapartum care for these women.

Regional anesthesia is acceptable for labor management and pain control since it is generally advisable to limit opiods, benzodiazipines and other sedatives that may contribute to respiratory depression. In women with severe disease or respiratory compromise, mechanical ventilation may be warranted.

Myasthenic patients show abnormal responses to both depolarizing and nondepolarizing agents. Myasthenics are relatively resistant to succinylcholine and therefore may call for larger doses, producing a prolonged block. Because acetylcholinesterase activity is altered in the myasthenic, the action of nondepolarizing agents is also increased. Myasthenics are more sensitive to the effects of certain inhalant anesthetics including enflurane, halothane, and isoflurane. Anticholinesterase may impair the hydrolysis of the ester-type local anesthetics; therefore, amide-type local anesthetics are preferable for regional block.

Consultation with Anesthesiology is recommended for women with MG prior to labor to better assess risks along with a management plan. Medication should be administered parenterally during labor due to erratic absorption and delayed gastric emptying. The parenteral dose of pyridostigmine is equivalent to 1/13th of the patient’s oral dose. Pharmacy should be involved with complicated medication changes.

Magnesium sulfate is commonly administered in obstetrics for the management of preeclampsia/eclampsia and preterm labor, but is relatively contraindicated in patients with MG since it can precipitate a severe myasthenic crisis. Severe hypertension can be managed with alpha methyl dopa and hydralazine, while beta blockers and calcium channel blockers should be avoided if possible. Valproic acid and phenobarbitol can be used for seizure prophylaxis, whereas phenytoin can potentially exacerbate weakness and is therefore reserved for refractory seizures.

The patient with MG and preeclampsia on high-dose steroids is at risk for pulmonary edema and should be monitored closely. Decreased urine output is commonly found in preeclamptic women, this may require dosage modifications in order to avoid toxicity.

Postpartum

During the postpartum period, the patient is best managed on the dosage of medication they were stable on before pregnancy. Medications that may exacerbate myasthenia gravis are listed in Table I.

4. Complications

Plasmapheresis is rarely used and often is reserved for those patients in myasthenia crisis or for short term treatment in those patients who are to undergo surgical thymectomy. Intravenous immune globulin is used for the same indications as plasmaphoresis.

5. Prognosis and outcome

The majority of myasthenic crises and fatalities occur within the first 2-3 years after diagnosis. Pregnancy does not alter the long term outcome of MG. The disease course in one pregnancy does not predict the disease course in subsequent pregnancies.

There is no increased risk of spontaneous abortion or fetal malformation in women with MG; however, since AChR antibodies are of the IgG type, they may cross the placenta and cause adverse fetal effects. Approximately 10-20% of newborns have transient MG due to transplacental passage of these antibodies. These newborns may have poor tone, respiratory depression and poor feeding. This may persist for up to 3 months and it is advisable to consult neonatal intensive care specialists for the birth of any infant born to a mother with MG.

Although data is limited, there is no correlation between neonatal MG and AChR antibody titer, nor does the dose or duration of treatment affect neonatal outcome. Neonatal MG has a recurrence rate of 75%. Abnormal fetal sonographic findings include polyhdramnios due to impaired swallowing, decreased fetal movement and in rare cases, fetal arthrogryposis multiplex congenita. This syndrome is described as a lack of fetal movement, diaphragmatic excursion, joint contractures and pulmonary hypoplasia.

What is the evidence for specific management and treatment recommendations